2-nitro-11-(1-piperazinyl)-dibenz(b,f)(1,4)oxazepines

ABSTRACT

2 - NITRO-11-(1-PIPERAZINYL)-DIBENZ(B,F)(1,4)OXAZEPINES AND ITS PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS ARE USEFUL AS ANTI-DEPRESSANTS.

ABSTRACT OF THE DISCLOSURE 2 nitro-1l-(1-piperazinyl)-dibenz[b,f][1,4]oxazepines and its pharmaceutically acceptable acid addition saltsare useful as anti-depressants.

This application is a continuation-in-part of our pending applicationSer. No. 57,316, filed July 22, 1970, now abandoned which in turn is acontinuation-in-part of application Ser. No. 797,281, filed Feb. 6,1969, which issued as U.S. Pat. 3,546,226 on Dec. 8, 1970 which in turnis a continuation-in-part of our earlier application Ser. No. 712,956,filed Mar. 14, 1968, now abandoned.

This invention is generally concerned with new heterocyclic compounds,and more specifically with 2-nitro-11- (1 piperazinyl) dibenz[b,f][l,4]oxazepine of the forand pharmaceutically acceptable acid additionsalts thereof. 2 nitro-11-( l-piperazinyl)-dibenz[b,f] [1,4] oxazepineis obtained when a compound of the formula:

wherein X denotes a residue capable of being split OE With the hydrogenof amines, is reacted with piperazine.

A residue capable of being split oif with the hydrogen of amines, whichcan be bound ionically or covalently to the carbon atom, can mostconveniently be represented by halogen, sulphydryl, or alkoxy andalkylthio which may be activated, e.g. methoxy, thiomethyl orp-nitrobenzylthio, or by tosyl.

Starting materials of the Formula II are obtained by converting thelactam of the formula:

NH-C o o (III) into the thiolactam which may be followed by alkylation,or by reaction of the lactam with a halogenating agent such asphosphorus oxychloride or phosphorus pentachloride, most suitably in thepresence of a catalytic amount of dimethylaniline or dimethylformamide.The lactam of United States Patent 0 Formula 111 is itself obtained byring closure of a compound of the formula:

wherein R denotes hydrogen or lower'alkyl. The lactam of Formula .IIImay also be obtained by ring closure of a compound of the formula:

NH-C O N 02 NCO N01 2 nitro-l1-(1-piperazinyl)-dibenz[b,f][1,4]oxazepineis further obtained by ring closure through intramoleeular condensationof an acid amide or acid thioamide of the formula:

/NH2 N on wherein Y represents oxygen or sulphur. A purely thermalcondensation rarely succeeds with the acid amide but rather with thethioamide which is, for example, obtained from the acid amide bytreatment with phosphorus pentasulphide and need not be isolated beforethe following condensation. Especially in the case of the acid amide itis desirable to perform the ring closure in the presence of condensingagents, such as phosphorus pentachloride, phosphorus oxychloride,phosgene, polyphosphoric acid, and the like. It is assumed that the ringclosure proceeds by way of intermediate steps such as imidochlorides,amidochlorides, imidophosphates, amidophosphates or salt-likederivatives thereof, which, in general, are not isolatable. Thecondensation of the thioamide is favoured by the presence of mercury(H)salts or by intermediate formation of imidothioethers which may beactivated. Heating and, if required, the use of a suitable inert solventare desirable, and when using phosphorus oxychloride and phosphoruspentachloride addition of catalytic amounts of dimethylformamide ordimethylaniline.

2-nitro-1 1-( 1-piperazinyl)-dibenz[b,f] 1,4]oxazepine is also obtainedby dehydration of an urea derivative of the formula:

NH- 0 LONG:

0 (VIII) wherein R means hydrogen or denotes a removable group,especially a hydrolytically removable group. The ring closure ispreferably carried out by heating in the presence of dehydrating agentssuch as zinc chloride, aluminium chloride, stannic chloride, phosphoricacid, polyphosphoric acid and the like, especially phosphorusoxychloride or phosphorus oxychloride and phosphorus pentoxide, ifdesired in an inert solvent of suitable boiling point such as benzene ortoluene, etc. According to the chosen reaction conditions the startingmaterial of Formula VIII with a hydrolytically removable group R e.g.,carbalkoxy, especially carbethoxy, is cyclicized directly to2-nitro-1l-(l-piperazinyl) compound by hydrol-" ysisof the removablegroup. Other removable groups can be split off after ring closure in away known per se, e.g., by hydrogenolysis.

2-nitro-11-(1 piperazinyl)-dibenz[b,f][1,4]oxazepine obtained in thismanner is crystallizable and reacts with inorganic and organic acidssuch as hydrochloric acid, hydrobromic acid, sulphuric acid, nitricacid, phosphoric acid, acetic acid, oxalic acid, maleic acid, succinicacid, tartaric acid, toluene sulphonic acid and the like to formaddition salts which are stable in water, in which form the product mayalso be used.

Analogous dibenz[b,f] [1,4] oxazepines are described in US. patentspecification No. 3,458,516 whose scope includes also the 2-nitro 11(1-piperazinyl) -di-benz[b,f] [1,4]oxazepine of the present invention.These compounds, especially those having a nitro substituent in abenzene nucleus show the typical pharmacological effects ofneuroleptics, which are seen e.g. in a reduction of the locomotoractivity of the test animals. It has been surprisingly found that the2-nitro-11-(1-piperazinyl)-dibenz [b,f] [1,4] oxazepine and its acidaddition salts of the present invention show besides a relatively strongreduction of the locomotor activity, an extremely intense tetrabenazineantagonising effects, which, according to Stille et al.,Arznei-mittelforschungl14, 534 if. (1964), is an indication for ananti-depressant action. Such as antidepressive activity has not beenobserved for any of the other compounds according to US. patentspecification No. 3,458,516. v

The 2-nitro-11-(1 piperazinyl)-dibenz[b,f] [1,4]oxazepine has in mice anED in the locomotor activity test [method of Caviezel and Baillod;Pharmac. Acta Helv. '33, 469 (1958)] of 2.4 mg./kg. p.o. The ED in theantitetrabenazine-test in rats (method of Stille; loc. cit.) is, for thecatalepsy 15.0 mg./kg. i.p. and for the ptosis 7.2 mg./kg. i.p. Themedian lethal dose LD in mice is 147 mg./ kg. p.o.

For use in the treatment of depression the compounds of this inventionmay be administered orally or parenterally as such or admixed withconventional pharmaceutical carriers. They may be administered orally insuch forms as tablets, dispersible powders, granules, capsules, syrupsand elixirs, and parenterally as solutions, suspensions, dispersions,emulsions, and the like, e.g., a sterileinjec'table aqueous suspension.The compositions for oral use may contain one or more conventionaladjuvants, such as sweetening agents, flavoring agents, coloring agentsand preserving agents, in order to provide an elegant and palatablepreparation. Tablets may contain theactive ingredient in admixture withconventional pharmaceutically acceptable excipients, e.g., inertdiluents, such as calcium carbonate, sodium carbonate, lactose and talc,granulating and disintegrating agents, e.g., starch and alginic acid,binding agents, e.g., starch, gelatin and acacia, and lubricatingagents, e.g., magnesium stearate, stearic acid and tale. The tablets maybe uncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. Similarly, suspensions, syrups and elixirsmay contain the active ingredient in admixture with any of theconventional excipients utilized for the preparation 01; suchcompositions, e.g., suspending agents (methylcellulose, tragacanth andsodium alginate),

'wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylenesorbitan monoleate) and preservatives (ethyl-p-hydroxybenzoate).Capsules may contain the active ingredient alone or admixed with aninert solid diluent, e.g., calcium carbonate, calcium phosphate andkaolin. The injectable compositions are formulated as known in the artand may contain appropriate dispersing or wetting agents and suspendingagents identical or similar to those mentioned above. Thesepharmaceutical preparations may contain up to about 90% of the activeingredient in combination with the carrier or adjuvant.

The anti-depressant effective dosage of active ingredient employed forthe treatment of depression may vary depending on the particularcompound employed and the severity of the condition 'being treated.However, in general, satisfactory results are obtained when thecompounds are administered at a daily dosage of firom about 0.07milligram to about 50 milligrams per kilogram of animal body weight p.o.For most large mammals in need of said treatment, the total daily dosageis from about 5 to about 400 milligrams. Dosage forms suitable forinternal use comprise from about 10 to about milligrams of the 1 activecompound in intimate admixture with a solid or containing about 10 to 25milligrams of active ingredient.

EXAMPLE 12.8 g. of 2-nitro-10,11-dihydro 11 -oxo-dibenz[b,f][l,'4]oxazepine M.P. 360 C.) and 5 ml. of N,N-dimethylaniline are heatedin 150 ml. of phosphorus oxychloride at reflux for 4 hours. The reactionmixture is then evaporated in vacuo to remove the excess phosphorusoxychloride and the residue is decomposed with ice/water and shaken outimmediately with xylene. The xylene phase is washed with dilutehydrochloric acid and water, dried over sodium sulphate, filteredthrough aluminium oxide and concentrated in vacuo to a volume of 70 ml.The reaction mixture so obtained is added during 2 hours dropwise to aboiling solution of 86.1 g. of anhydrous piperazine in 800 ml. of xyleneand 50 ml. of dioxane and heated at reflux for 4 hours. The reactionmixture is poured onto ice/water and rendered alkaline with concentratedsoda lye. The xylene phase is washed with water and extracted with 2 Nsulphuric acid. The sulphuric acid extracts are washed with toluene andrendered alkaline with concentrated soda lye and the base whichseparates is extracted with methylene chloride. The organic phase iswashed with water, dried over sodium sulphate, filtered throughaluminium oxide and evaporated to dryness in vacuo. The residue iscrystallized from acetone/petroleum ether and gives 12 g. of2-nitro-11-(1- piperazinyl)-dibenz[b,f][1,4]oxazepine of M.P. 190 192 C.

Production of tablets For the manufacture of tablets, the products ofthis invention can be mixed with lactose and granulated with water, 0.5%sodium alginate or 1% gelative solution. The dried granulate iscompressed into tablets in the presence of about 5% of talcum, 5% ofcorn starch and 0.1% of magnesium stearate. In this way, there areobtained, e.g. tablets of the following composition:

I These mg. tablets, which are provided with a crackline, can beadministered orally in the dosage of /2 to 2 tablets 2 to 5 times, insome cases up to 5 times 4 tablets .per day in the treatment of subjectssuffering from states of mental depression and especially agitated formsof depression.

Sterile suspension for injection andoral liquid suspension PIIIPOSC.

Weight (mg.)

Sterile Oral injeetable liquid Ingredients suspension suspension Sodiumearboxy methyl cellulose U.S.P.

Methyl cellulose Polyvinylpyrrolidone Tmoirhin Benzyl alcohol Magnesiumaluminum silicate- Flavor. Color Methyl paraben, U.S.P Propyl parabeuU.S.P Polysorbate 80 (e.g. Tween 80), U P Sorbital solution, 70%, U.S.P

vlvu fler agent to adjust pH for desired stability- 1 For injection q.s.to 1 mi. I Q.s. to 5 m1.

Capsules suitable for oral administration Capsules containing theingredients indicated below may be prepared by conventional techniquesand are useful in treating depression at a dose of one tablet, ofcapsule, 2 to 4 times a day.

Ingredient: Capsule weight (mg.) 2 nitro 11(piperazinyl)-dibenz[b,f][1,4]

oxazepine Lactose 290 Total 300 What we claim is:

1. 2 nitro 11 (1 piperazinyl) dibenz[b,f][1,4] oxazepine and itspharmaceutically acceptable acid addition salts.

References Cited UNITED STATES PATENTS 3,660,406 5/1972 Howell 260-268TR 3,697,523 10/1972 Hunziker 260268 TR 3,705,245 12/1972 Howell 260268TR DONALD G. DAUS, Primary Examiner US. Cl. X.R. 424-250

